Ovarian epithelial cancer is the leading cause of death from cancers of female reproductive tract, yet the pathogenesis of the disease is still poorly understood. A growing body of epidemiological evidence suggests that ovarian carcinogenesis may be related to risk factors causing chronic epithelial inflammation. Chronic inflammation has been hypothesized to be involved in cancer development because it promotes growth, invasion, angiogenesis, reactive oxygen species production and suppression of host-defense mechanisms. Several risk factors implicated in ovarian cancer development such as pelvic inflammatory disease, endometriosis, and incessant ovulation, an inflammation-like process, support the hypothesis that inflammation is important in ovarian cancer etiology. Conversely, factors that suppress ovulation (pregnancy, lactation, and use of oral contraceptives) and possibly use of anti-inflammatory medications are associated with reduced risk. These observations led to the suggestion that inflammatory processes play a significant etiologic role in ovarian cancer. We propose to test the hypothesis that the conditions and risk factors characterized by shift to the pro-inflammatory state may increase the risk of epithelial ovarian cancer and, consequently, that circulating markers of inflammation may be directly associated with risk of epithelial ovarian cancer. lentvly, anti-inflammatory markers, which regulate the pro- inflammatory response, are expected to be inversely associated with epithelial ovarian cancer risk. To address these hypotheses, we propose a case-control study nested within three on- going collaborating prospective cohort studies: 1) the New York University Women's Health Study (NYUWHS);2) the Northern Sweden Health and Disease Study (NSHDS);and 3) the Italian Hormones and Diet in the Etiology of Cancer (ORDET). The participating cohorts have assembled a large volume of baseline and follow-up information on all study members and have access to a valuable repository of blood specimens from all individuals, including serum and plasma samples. The long-term objective of the current application is to develop a panel of novel circulating markers for identification of women at high-risk for ovarian cancer, who subsequently may benefit from more inesve screening for earlier detection of the disease. PUBLIC HEALTH RELEVANCE: The long-term objective of the current application is to develop a panel of new serum markers for identification of women at high-risk for ovarian cancer, who subsequently may benefit from more invasive screening for earlier detection of the disease. The results of the study could be particularly important for development of new approaches to identify women at risk and may provide additional support for development of novel ovarian cancer preventive strategies using anti-inflammatory medications.